Ophthalmic compositions comprising combinations of a carbonic anhydrase inhibitor and a β-adrenergic antagonist

ABSTRACT

Combinations of a β-adrenergic antagonist and a topical carbonic anhydrase inhibitor are particularly useful in the treatment of ocular hypertension, especially in patients insufficiently responsive to treatment with β-adrenergic antagonists.

This is a continuation of application Ser. No. 08/587,698 filed on Jan.17, 1996, now abandoned, which is a continuation of application Ser. No.08/286,157 filed Aug. 4, 1994, now abandoned.

SUMMARY OF THE INVENTION

This invention relates to novel ophthalmic compositions comprising atopical carbonic anhydrase inhibitor of structure:

wherein A, Z, R¹ and X are as hereinafter defined, or anophthamologically acceptable salt thereof and a β-adrenergic antagonistselected from betaxolol, bufenolol, carteolol, levobunolol,metipranolol, and timolol, or an ophthalmologically acceptable saltthereof.

The invention is also concerned with the use of the novel ophthalmiccompositions in the treatment of ocular hypertension.

More particularly, it relates to such ophthalmic combinations and theiruse in the treatment of ocular hypertension and glaucoma, wherein theβ-adrenergic antagonist is1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol,or an ophthalmologically acceptable salt thereof which name includes the(S)-(−)- and (R)-(+)-enantiomers and any mixtures thereof, includingracemic material. The (S)-(−)-enantiomer is generally known as timolol.

BACKGROUND OF THE INVENTION

Glaucoma is a degenerative disease of the eye wherein the intraocularpressure is too high to permit normal eye function. As a result, damagemay occur to the optic nerve head and result in irreversible loss ofvisual function. If untreated, glaucoma may eventually lead toblindness. Ocular hypertension, i.e., the condition of elevatedintraocular pressure without optic nerve head damage or characteristicglaucomatous visual field defects, is now believed by the majority ofophthalmologists to represent merely the earliest phase in the onset ofglaucoma.

Many of the drugs formerly used to treat glaucoma proved not entirelysatisfactory. The early methods of treatment of glaucoma employingpilocarpine produced undesirable local effects that made this drug,though valuable, unsatisfactory as a first line drug. More recently,clinicians have noted that many β-adrenergic antagonists are effectivein reducing intraocular pressure. While many of these agents areeffective for this purpose, there exist some patients with whom thistreatment is not effective or not sufficiently effective. Many of theseagents also have other characteristics, e.g., membrane stabilizingactivity, that become more apparent with increased doses and render themunacceptable for chronic ocular use.

The β-adrenergic antagonist(S)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol,timolol, was found to reduce intraocular pressure and to be devoid ofmany unwanted side effects associated with pilocarpine and, in addition,to possess advantages over many other β-adrenergic antagonists, e.g., tobe devoid of local anesthetic properties, to have a long duration ofactivity, and to display minimal loss of effect with increased durationof dosing.

Although pilocarpine and β-adrenergic antagonists reduce intraocularpressure, none of these drugs manifests its action by inhibiting theenzyme carbonic anhydrase, and thus they do not take advantage ofreducing the contribution to aqueous humor formation made by thecarbonic anhydrase pathway.

Agents referred to as carbonic anhydrase inhibitors block or impede thisinflow pathway by inhibiting the enzyme carbonic anhydrase. While suchcarbonic anhydrase inhibitors are now used to treat intraocular pressureby systemic routes, they thereby have the distinct disadvantage ofinhibiting carbonic anhydrase throughout the entire body. Such a grossdisruption of a basic enzyme system is justified only during an acuteattack of alarmingly elevated intraocular pressure, or when no otheragent is effective.

For several years, the desirability of directing the carbonic anhydraseinhibitor to only the desired ocular target tissue has been recognized.Because carbonic anhydrase inhibitors have a profound effect in alteringbasic physiological processes, the avoidance of a systemic route ofadministation serves to diminish, if not entirely eliminate, those sideeffects caused by inhibition of carbonic anhydrase such as metabolicacidosis, vomiting, numbness, tingling, general malaise and the like.Topically effective carbonic anhydrase inhibitors are disclosed in U.S.Pat. Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; and 4,863,922 andPCT Publication WO 91/15486. As yet, no topically effective carbonicanhydrase inhibitors are generally available for clinical use.

Thus, when a carbonic anhydrase inhibitor is combined with aβ-adrenergic antagonist, there is experienced an effect that reduces theintraocular pressure below that obtained by either medicamentindividually.

The activity of carbonic anhydrase inhibitors currently underdevelopment wanes 6 to 8 hours post-dose, meaning that as single agentsthese carbonic anhydrase inhibitors must be administered at least threetimes a day to maintain the desired lowering of intraocular pressure.The combination of this invention maintains the desired lowering ofintraocular pressure for a full twelve hours. Because of this increasedduration of action, the combination disclosed herein is effective whenadministered only twice a day. Patient compliance is anticipated to begreater with twice a day administration than with three times a dayadministration.

The use of oral carbonic anhydrase inhibitors in combination with thetopical β-adrenergic antagonist timolol and the resulting multiplicityof their effects is disclosed in Berson et al., American Journal ofOphthalmology 1981, 92, 788-791. However, the combination of an oralcarbonic anhydrase inhibitor with a topical β-adrenergic antagonistpresents two disadvantages. The first disadvantage is that the systemicuse of a carbonic anhydrase inhibitor inhibits carbonic anhydrasethroughout the body and exerts the same profound negative effects onbasic metabolism whether it is used alone or in combination with atopical β-adrenergic antagonist. Secondly, there is poor patientcompliance with simultaneous administration of both an oral and topicalmedicament.

The combination disclosed herein is effective either byco-administration of the medicaments in one solution or as a combinedtherapy achieved by prior administration of either the carbonicanhydrase inhibitor or the β-adrenergic antagonist followed byadministration of the other solution. The use of a single solutioncontaining both active medicaments is preferred.

The combination of this invention is suggested in U.S. Pat. No.4,863,922, but a precise formulation of the relative combination ofmedicaments to give effective reduction of intraocular pressure isneither taught nor disclosed therein.

There exists a patient population insufficiently responsive to availableβ-adrenergic antagonists who will benefit from the combination disclosedherein. Because of the combined effect of the β-adrenergic antagonistand the carbonic anhydrase inhibitor, these otherwise refractorypatients can obtain a marked beneficial reduction in intraocularpressure from such a combination.

Furthermore, there exists a patient population who will benefit from acombination where the minimal dosage of one or both of the medicamentsis employed, thus minimizing the possibility of the occurrence ofundesirable effects of one or both of the medicaments which would bemore likely to become apparent with chronic use at the higher dosage.

DETAILED DESCRIPTION OF THE INVENTION

The novel ophthalmic compositions of this invention comprise atherapeutically effective amount of a topical carbonic anhydraseinhibitor and a β-adrenergic antagonist. The topical carbonic anhydraseinhibitor of the novel composition has the structural formula:

or an ophthalmologically acceptable salt thereof wherein:

A is carbon or nitrogen, preferably carbon;

Z is —NHR or —OR;

R is C₁₋₆ alkyl, either straight or branched chain, preferably C₂₋₄alkyl such as ethyl, propyl or isobutyl;

R¹ is

(a) hydrogen,

(b) C₁₋₃ alkyl, preferably methyl, ethyl or n-propyl, or

(c) C₁₋₄ alkoxy-C₁₋₄ alkyl, preferably methoxypropyl; and

X is —S(O)₂— or —C(O)₂—.

The carbon atoms to which Z and R¹ are bonded may be chiral. When namedaccording to absolute configuration, e.g., (R,S) or (S,S), the firstletter represents the chirality the carbon atom to which Z is bonded andthe second letter represents the charality of A when A is carbon. Thecarbonic anhydrase inhibitors of this invention accordingly may be usedas diastereomeric mixtures or single enantiomers or as racemic mixtures.

The β-adrenergic antagonist of the novel composition is selected frombetaxolol, bufenolol, carteolol, levobunolol, metipranolol, and timolol,or an ophthalmologically acceptable salt thereof.

Most of the β-adrenergic antagonists and carbonic anhydrase inhibitorsrecited above have at least one asymmetric carbon atom and accordinglymay exist as diastereomers or (+)- or (−)-enantiomers. This inventioncontemplates the use of any of the diastereomers or enantiomers ormixtures thereof including racemic forms.

The preferred β-adrenergic antagonist for use in the novel compositionof this invention is timolol as its maleate salt.

The novel ophthalmic formulations of this invention comprise about 0.05to 5% (w/w) of carbonic anhydrase inhibitor, usually about 0.5 to 3%(w/w) and about 0.01 to 1% (w/w) of β-adrenergic antagonist, preferablyabout 0.1 to 0.5% (w/w) to be administered on a 1 to 2 times a dayschedule.

The novel method of this invention comprises the topical ocularadministration of about 0.025 to 5 mg per day, preferably about 0.25 to3 mg per day, of carbonic anhydrase inhibitor and concomitant, prior, orprevious administration of about 0.005 to 1 mg per day, preferably about0.05 to 0.5 mg per day, of β-adrenergic antagonist to each eye.

As a unit dosage, between 0.025 and 2.5 mg of the carbonic anhydraseinhibitor and 0.005 to 0.5 mg of the β-adrenergic antagonist are appliedto the eye; preferably, 0.25 to 1.5 mg of the carbonic anhydraseinhibitor and 0.05 to 0.25 mg of the β-adrenergic antagonist.

Suitable subjects for the administration of the formulation of thepresent invention include primates, man and other animals, particularlyman and domesticated animals such as cats and dogs.

For topical ocular administration the novel formulations of thisinvention may take the form of solutions, gels, ointments, suspensionsor solid inserts, formulated so that a unit dosage comprises atherapeutically effective amount of each active component or somesubmultiple thereof.

Typical ophthalmologically acceptable carriers for the novelformulations are, for example, water, mixtures of water andwater-miscible solvents such as lower alkanols or aralkanols, vegetableoils, polyalkylene glycols, petroleum based jelly, ethyl cellulose,ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropylmyristate and other conventionally employed acceptable carriers. Thepharmaceutical preparation may also contain non-toxic auxiliarysubstances such as emulsifying, preserving, wetting agents, bodyingagents and the like, as for example, polyethylene glycols 200, 300, 400and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterialcomponents such as quaternary ammonium compounds, phenylmercuric saltsknown to have cold sterilizing properties and which are non-injurious inuse, thimerosal, benzalkonium chloride, methyl and propyl paraben,benzyldodecinium bromide, benzyl alcohol, phenylethanol, bufferingingredients such as sodium chloride, sodium borate, sodium acetate, orgluconate buffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate,dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol,ethylenediamine tetra-acetic acid, and the like. Additionally, suitableophthalmic vehicles can be used as carrier media for the present purposeincluding conventional phosphate buffer vehicle systems, isotonic boricacid vehicles, isotonic sodium chloride vehicles, isotonic sodium boratevehicles and the like.

The formulation may also include a gum such as gellan gum at aconcentration of 0.1 to 2% by weight so that the aqueous eyedrops gel oncontact with the eye, thus providing the advantages of a solidophthalmic insert as described in U.S. Pat. No. 4,861,760.

The pharmaceutical preparation may also be in the form of a solid insertsuch as one which after dispensing the drug remains essentially intactas described in U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874; or abio-erodible insert that either is soluble in lacrimal fluids, orotherwise disintegrates as described in U.S. Pat. No. 4,287,175 or EPOpublication 0,077,261.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows percent change in intraocular pressure (10 p) from prestudyat hours post dose.

The following examples of ophthalmic formulations are given by way ofillustration.

EXAMPLE 1

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-ethyl- 22.26 g22.26 g 1.113 g amino-6-methyl-4H-thieno- [2,3b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride (S)-(-)-1-(tert-butylamino)- 6.834 g 1.367g 6.834 g 3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanolmaleate Sodium citrate.2H₂O 2.940 g 2.940 g 2.940 g BenzalkoniumChloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 50%W/W solution), and mannitol are dissolved in approximately 400 mL waterfor injection in a tared and sterile vessel. The pH of the compositionis adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution, andwater for injection is added until the weight of composition equals 750g. The composition is sterilized by filtration, pushing the solutionwith a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a2% hydroxyethylcellulose autoclaved solution is added and the obtainedsolution is homogenized by stirring with a magnetic stirring bar. Thesolution is aseptically subdivided into 3.5 mL aliquots and sealed.

EXAMPLE 2

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-ethyl- 1.0 mg 1.5mg 0.5 mg amino-6-methyl-4H-thieno- (2,3b]thiopyran-2-sulfonamide-7,7-dioxide 4-[2-hydroxy-3-(1-methylethyl)- 0.3 mg 0.2 mg 0.4 mgamino]-propoxy]-2,3,6- trimethylphenol-1-acetate Monobasic sodiumphosphate Quantity sufficient 2H₂O to give Dibasic sodium phosphatefinal pH 5.5-6.0 .12H₂O Benzalkonium chloride 0.10 mg 0.10 mg 0.10 mgPolysorbate 80 0.2 mg 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, benzalkonium chloride, andPolysorbate 80 are added to and suspended or dissolved in water. The pHof the composition is adjusted to 5.5-6.0 and diluted to volume. Thecomposition is rendered sterile by filtration through a sterilizingfilter.

EXAMPLE 3

SOLUTION COMPOSITION I II trans-5,6-dihydro-4-ethylamino- 1.7 mg 0.8 mg6-methyl-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide1-[4-[2-(cyclopropylmethoxy)- 0.3 mg 0.2 mgethyl]phenoxy]-3-(1-methylethyl)- amino]-2-propanol Monobasic sodiumphosphate.2H₂O 9.5 mg 9.5 mg Dibasic sodium phosphate.12H₂O 28.5 mg 28.5mg Benzalkonium chloride 0.10 mg 0.10 mg Sodium hydroxide q.s. ad. pH6.0 pH 6.0 Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, and benzalkonium chlorideare added to and dissolved in water. The pH of the composition isadjusted to 6.0 with sodium hydroxide and the final solution is dilutedto volume. The solution is rendered sterile by filtration through asterilizing filter.

EXAMPLE 4

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-propyl- 21.0 g21.0 g 1.5 g amino-6-methoxypropyl-4H-thieno-[2,3b]thiopyran-2-sulfonamide- 7,7-dioxide monohydrochloride(S)-(-)-1-(tert-butylamino)- 6.8 g 1.3 g 6.8 g 3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxyl-2- propanol maleate Sodium citrate.2H₂O 2.9 g 2.9 g2.9 g Benzalkonium Chloride 0.075 g 0.075 g 0.075 gHydroxyethylcellulose 5.0 g 5.0 g 5.0 g Sodium hydroxide q.s. pH = 6.0pH = 6.0 pH = 6.0 Mannitol 35.9 g 35.9 g 35.9 g Water for injection q.s.ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 50%W/W solution), and mannitol are dissolved in approximately 400 mL waterfor injection in a tared and sterile vessel. The pH of the compositionis adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution andwater for injection is added until the weight of composition equals 750g. The composition is sterilized by filtration, pushing the solutionwith a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a2% hydroxyethylcellulose autoclaved solution is added and the obtainedsolution is homogenized by stirring with a magnetic stirring bar. Thesolution is aseptically subdivided into 3.5 mL aliquots and sealed.

EXAMPLE 5

SOLUTION COMPOSITION I II III (S,S)-(-)-5,6-dihydro-4-propylamino- 1.0mg 1.5 mg 0.5 mg 6-methoxypropyl-4H-thieno[2,3b]thiopyran-2-sulfonamide-7,7- dioxide 4-[2-hydroxy-3-(1-methylethyl)- 0.3mg 0.2 mg 0.4 mg amino]propoxy]-2,3,6- trimethylphenol-1-acetateMonobasic sodium phosphate Quantity sufficient .2H₂O to give Dibasicsodium phosphate final pH 5.5-6.0 .12H₂O Benzalkonium chloride 0.10 mg0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, benzalkonium chloride, andPolysorbate 80 are added to and suspended or dissolved in water. The pHof the composition is adjusted to 5.5-6.0 and diluted to volume. Thecomposition is rendered sterile by filtration through a sterilizingfilter.

EXAMPLE 6

SOLUTION COMOSITION I II trans-5,6-digydro-4-propylamino- 1.7 mg 0.8 mg6-methoxypropyl-4H-thieno[2,3b] thiopyran-2-sulfonamide-7,7- dioxide1-[4-[2-(cyclopropylmethoxy)ethyl]- 0.3 mg 0.2 mgphenoxy]-3-(1-methylethyl)amino]- 2-propanol Monobasic sodiumphosphate.2H₂O 9.5 mg 9.5 mg Dibasic sodium phosphate.12H₂O 28.5 mg 28.5mg Benzalkonium chloride 0.10 mg 0.10 mg Sodium hydroxide q.s. pH 6.0 pH6.0 Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, and benzalkonium chlorideare added to and dissolved in water. The pH of the composition isadjusted to 6.0 with sodium hydroxide and the final solution is dilutedto volume. The solution is rendered sterile by filtration through asterilizing filter.

EXAMPLE 7

SOLUTION COMPOSITION I II III (S)-(+)-5,6-dihydro-4-isobutyl- 21.0 g21.0 g 1.5 g amino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxidemono- hydrochloride (S)-(-)-1-(tert-butylamino)- 6.8 g 1.3 g 6.8 g3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.9 g 2.9 g 2.9 g Benzalkonium Chloride 0.075 g 0.075 g0.075 g Hydroxyethylcellulose 5.0 g 5.0 g 5.0 g Sodium hydroxide q.s. pH= 6.0 pH = 6.0 pH = 6.0 Mannitol 35.9 g 35.9 g 35.9 g Water forinjection q.s. ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 50%W/W solution), and mannitol are dissolved in approximately 400 mL waterfor injection in a tared and sterile vessel. The pH of the compositionis adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution andwater for injection is added until the weight of composition equals 750g. The composition is sterilized by filtration, pushing the solutionwith a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a2% hydroxyethylcellulose autoclaved solution is added and the obtainedsolution is homogenized by stirring with a magnetic stirring bar. Thesolution is aseptically subdivided into 3.5 mL aliquots and sealed.

EXAMPLE 8

SOLUTION COMPOSITION I II III (S)-(+)-5,6-dihydro-4-isobutyl- 1.0 mg 1.5mg 0.5 mg amino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide4-[2-hydroxy-3-(1-methylethyl)- 0.3 mg 0.2 mg 0.4 mgamino]propoxyl-2,3,6- trimethylphenol-1-acetate Monobasic sodiumphosphate Quantity sufficient .2H₂O to give Dibasic sodium phosphatefinal pH 5.5-6.0 .12H₂O Benzalkonium chloride 0.10 mg 0.10 mg 0.10 mgPolysorbate 80 0.2 mg 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, benzalkonium chloride, andPolysorbate 80 are added to and suspended or dissolved in water. The pHof the composition is adjusted to 5.5-6.0 and diluted to volume. Thecomposition is rendered sterile by filtration through a sterilizingfilter.

EXAMPLE 9

SOLUTION COMPOSITION I II (S)-(+)-5,6-dihydro-4-isobutyl- 1.7 mg 0.8 mgamino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide1-[4-[2-(cyclopropylmethoxy)- 0.3 mg 0.2 mgethyl]-phenoxy]-3-(1-methylethyl)- amino]-2-propanol Monobasic sodiumphosphate.2H₂O 9.5 mg 9.5 mg Dibasic sodium phosphate.12H₂O 28.5 mg 28.5mg Benzalkonium chloride 0.10 mg. 0.10 mg Sodium hydroxide q.s. pH 6.0pH 6.0 Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, phosphate buffer salts, and benzalkonium chlorideare added to and dissolved in water. The pH of the composition isadjusted to 6.0 with sodium hydroxide and the final solution is dilutedto volume. The solution is rendered sterile by filtration through asterilizing filter.

EXAMPLE 10

SOLUTION CONPOSITION I II (S,S)-(-)-5,6-dihydro-4-ethyl- 2.0 mg 0.2 mgamino-6-methyl-4H-thieno[2,3b]- thiopyran-2-sulfonamide-7,7- dioxidemonohydrochloride (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 11

SOLUTION COMPOSITION I II (S)-(+)-5,6-dihydro-4-isobutyl- 3.0 mg 0.5 mgamino-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide(S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg 3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate GELRITE ™ gellan gum 6.0 mg 6.0mg Monobasic sodium phosphate Quantity sufficient .2H₂O to give Dibasicsodium phosphate final pH 5.0-6.0 .12H₂O Benzyldodecinium bromide 0.10mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.0-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 12

SOLUTION COMPOSITION I II (S,S)-(-)-5,6-dihydro-4-propyl- 2.0 mg 0.2 mgamino-6-methoxypropyl-4H- thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 13

SOLUTION COMPOSITION I II (R)-(-)-5,6-dihydro-4-iso- 2.0 mg 0.5 mgbutylamino-4H-thieno[2,3b]-thio- pyran-2-sulfonamide-7,7-dioxide4-[2-hydroxy-3-(1-methylethyl) 0.5 mg 0.5 mg amino]propoxy]-2,3,6-trimethylphenol-1-acetate GELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasicsodium phosphate Quantity sufficient .2H₂O to give Dibasic sodiumphosphate final pH 5.5-6.0 .12H₂O Benzyldodecinium bromide 0.10 mg 0.10mg Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0 mL 1.0mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 14

SOLUTION COMPOSITION I II cis-5,6-dihydro-4-ethylamino- 2.0 mg 0.2 mg6-methyl-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxidemonohydrochloride 4-[2-hydroxy-3-(1-methlethyl)- 0.5 mg 0.5 mgamino]propoxy]-2,3,6- trimethylphenol-l-acetate GELRITE ™ gellan gum 6.0mg 6.0 mg Monobasic sodium phosphate Quantity sufficient .2H₂O to giveDibasic sodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodeciniumbromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 15

SOLUTION COMPOSITION I II cis-5,6-dihydro-4-propyl- 2.0 mg 0.5 mgamino-6-methoxypropyl-4H- thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide 4-[2-hydroxy-3-(1-methylethyl)- 0.5 mg 0.5 mgamino]propoxy]-2,3,6- trimethylphenol-1-acetate GELRITE ™ gellan gum 6.0mg 6.0 mg Monobasic sodium phosphate Quantity sufficient .2H₂O to giveDibasic sodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodeciniumbromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 16

SOLUTION COMPOSITION I II 5,6-dihydro-4-ethylamino- 2.0 mg 0.2 mg6-methyl-4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxidemonohydrochloride 1-[4-[2-(cyclopropylmethoxy)ethyl]- 0.5 mg 0.5 mgphenoxy]-3-(1-methylethyl)amino]- 2-propanol GELRITE ™ gellan gum 6.0 mg6.0 mg Monobasic sodium phosphate Quantity sufficient .2H₂O to giveDibasic sodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodeciniumbromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 17

SOLUTION COMPOSITION I II 5,6-dihydro-4-isobutylamino- 2.0 mg 0.5 mg4H-thieno[2,3b]thiopyran- 2-sulfonamide-7,7-dioxide1-[4-[2-(cyclopropylmethoxy)ethyl]- 0.5 mg 0.5 mgphenoxy]-3-(1-methylethyl)amino]- 2-propanol GELRITE ™ gellan gum 6.0 mg6.0 mg Monobasic sodium phosphate Quantity sufficient .2H₂O to giveDibasic sodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodeciniumbromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 18

SOLUTION COMPOSITION I II 5,6-dihydro-4-propylamino- 2.0 mg 0.2 mg6-methoxypropyl-4H- thieno[2,3b]thiopyran-2- sulfonamide-7,7-dioxide1-[4-[2-(cyclopropylmethoxy)ethyl]- 0.5 mg 0.5 mgphenoxy]-3-(1-methylethyl)amino]- 2-propanol GELRITE ™ gellan gum 6.0 mg6.0 mg Monobasic sodium phosphate Quantity sufficient .2H₂O to giveDibasic sodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodeciniumbromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injectionq.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 19

SOLUTION COMPOSITION I II III 3,4-Dihydro-4-methoxy-2-methyl- 22.26 g22.26 g 1.113 g 2H-thieno[3,2-e]-1,2-thiazine- 6-sulfonamide-1,1-dioxide(S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834 g3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxideq.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Waterfor injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 20

SOLUTION COMPOSITION I II III 3,4-Dihydro-4-ethylamino-2- 22.26 g 22.26g 1.113 g methyl-2H-thieno[3,2-e]-1,2- thiazine-6-sulfonamide-1,1-dioxide hydrochloride (S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834g 3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateSodium citrate.2H₂O 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodiumhydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90g Water for injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 21

SOLUTION COMPOSITION I II III 3,4-Dihydro-methyl-4-(2- 22.26 g 22.26 g1.113 g methyl)propylamino-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfon-amide-1,1-dioxide hydrochloride (S)-(-)-1-(tert-butylamino)- 6.834 g1.367 g 6.834 g 3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanolmaleate Sodium citrate.2H₂O 2.940 g 2.940 g 2.940 g BenzalkoniumChloride 0.075 g 0.075 g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g5.00 g Sodium hydroxide q.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g21.00 g 35.90 g Water for injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 22

SOLUTION COMPOSITION I II III R-(+)-3,4-Dihydro-4-ethylamino- 22.26 g22.26 g 1.113 g 2-methyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1- dioxide hydrochloride(S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834 g3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxideq.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Waterfor injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 23

SOLUTION COMPOSITION I II III R-(+)-3,4-Dihydro-4-ethylamino- 22.26 g22.26 g 1.113 g 2-(2-methoxy)ethyl-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfon- amide-1,1-dioxide hydrochloride(S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834 g3-[(4morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxideq.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Waterfor injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 24

SOLUTION COMPOSITION I II III R-(+)-3,4-Dihydro-2-(2-methoxy)- 22.26 g22.26 g 1.113 g ethyl-4-propylamino-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfon- amide-1,1-dioxide hydrochloride(S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834 g3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.946 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxideq.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Waterfor injection q.s. ad. 1000 g 1000 g 1000 g

EXAMPLE 25

SOLUTION COMPOSITION I II 3,4-Dihydro-4-methoxy-2-methyl- 2.0 mg 0.2 mg2H-thieno[3,2-e]-1,2-thiazine- 6-sulfonamide-1,1-dioxide(S)-(-)-1-(tert-butylamino)- 1.5 mg 0.5 mg 3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate GELRITE ™ gellan gum 6.0 mg 6.0mg Monobasic sodium phosphate Quantity sufficient .2H₂O to give Dibasicsodium phosphate final pH 5.5-6.0 .12H₂O Benzyldodecinium bromide 0.10mg 0.10 mg Polysorbate 80 0.2 mg 0.2 mg Water for injection q.s. ad. 1.0mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 26

SOLUTION COMPOSITION I II 3,4-Dihydro-4-methylamino-2- 2.0 mg 0.2 mgmethyl-2H-thieno[3,2-e]- 1,2-thiazine-6-sulfonamide- 1,1-dioxidehydrochloride (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 27

SOLUTION COMPOSITION I II 3,4-Dihydro-2-methy-4-(2- 2.0 mg 0.2 mgmethyl)propylamino-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfon-amide-1,1-dioxide hydrochloride (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5mg 3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 28

SOLUTION COMPOSITION I II R-(+)-3,4-Dihydro-4-ethyl- 2.0 mg 0.2 mgamino-2-methyl-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfon-amide-1,1-dioxide hydrochloride (S)-(-)-1-tert-butylamino)- 0.5 mg 0.5mg 3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 29

SOLUTION COMPOSITION I II R-(+)-3,4-Dihydro-4-ethyl- 2.0 mg 0.2 mgamino-2-(2-methoxy)ethyl-2H- thieno[3,2-e]-1,2-thiazine-6- sulfonamide1,1-dioxide hydro- chloride (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 30

SOLUTION COMPOSITION I II R-(+)-3,4-Dihydro-2-(2-methoxy)- 2.0 mg 0.2 mgethyl-4-propylamino-2H-thieno- [3,2-e]-1,2-thiazine-6-sulfon- amide1,1-dioxide hydrochloride- (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic Sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 31

SOLUTION CONPOSITION I II III (S,S)-(-)-5,6-dihydro-4-ethyl- 22.26 g22.26 g 1.113 g amino-6-propyl-4H-thieno- [2,3b]thiopyran-2-sulfonamide- 7,7-dioxide monohydrochloride(S)-(-)-1-(tert-butylamino)- 6.834 g 1.367 g 6.834 g3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleate Sodiumcitrate.2H₂O 2.940 g 2.940 g 2.940 g Benzalkonium Chloride 0.075 g 0.075g 0.075 g Hydroxyethylcellulose 5.00 g 5.00 g 5.00 g Sodium hydroxideq.s. pH = 6.0 pH = 6.0 pH = 6.0 Mannitol 16.00 g 21.00 g 35.90 g Waterfor injection q.s. ad. 1000 g 1000 g 1000 g

The active compounds, sodium citrate, benzalkonium chloride (in a 50%W/W solution), and mannitol are dissolved in approximately 400 mL waterfor injection in a tared and sterile vessel. The pH of the compositionis adjusted to 6.0 by addition of 0.2 N sodium hydroxide solution, andwater for injection is added until the weight of composition equals 750g. The composition is sterilized by filtration, pushing the solutionwith a 2 bar pressure of 0.45 micron filtrated nitrogen. Then 250 g of a2% hydroxyethylcellulose autoclaved solution is added and the obtainedsolution is homogenized by stirring with a magnetic stirring bar. Thesolution is aseptically subdivided into 3.5 mL aliquots and sealed.

EXAMPLE 32

SOLUTION COMPOSITION I II (S,S)-(-)-5,6-dihydro-4-ethyl- 2.0 mg 0.2 mgamino-6-propyl-4H-thieno- [2,3b]thiopyran-2-sulfonamide- 7,7-dioxidemonohydrochloride (S)-(-)-1-(tert-butylamino)- 0.5 mg 0.5 mg3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2- propanol maleateGELRITE ™ gellan gum 6.0 mg 6.0 mg Monobasic sodium phosphate Quantitysufficient .2H₂O to give Dibasic sodium phosphate final pH 5.5-6.0.12H₂O Benzyldodecinium bromide 0.10 mg 0.10 mg Polysorbate 80 0.2 mg0.2 mg Water for injection q.s. ad. 1.0 mL 1.0 mL

The active compounds, GELRITE™ gellan gum, phosphate buffer salts,benzyldodecinium bromide and Polysorbate 80 are added to and suspendedor dissolved in water. The pH of the composition is adjusted to 5.5-6.0and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 33 Study of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3b]thiopyran-2-sulfonamide-7,7-dioxide(I) in combination with Timolol

Patients aged 40 or over, with either ocular hypertension or primaryopen angle glaucoma with an intraocular pressure (IOP) in one or botheyes of 22 mmHg or more at one time point each day while receivingtimolol 0.5% twice a day (bid) alone were admitted to the study.Patients had been on timolol 0.5% bid, either alone or in combinationfor at least three weeks prior to study entry and had been on timolol0.5% bid as their sole glaucoma therapy for at least two weeks prior tostudy admission.

Secondary glaucoma was an exclusion as was a history of glaucoma surgeryor laser trabeculoplasty/gonioplasty. Patients for whom timolol wascontraindicated by the datasheet were excluded and also excluded werethose on a concurrent β-blocker, carbonic anhydrase inhibitor, orclonidine. Thirty-one patients entered the study.

Procedure

1. All patients had their visual fields plotted by Goldmann Perimetryprior to study entry.

2. Patients were admitted for a 12 hour diurnal curve (i.e., IOPrecorded at 08.00, 09.00, 10.00, 12.00, 14.00, 16.00, 18.00, 20.00 hoursapproximately, the 08.00 recording was immediately prior to instillationof the drops). All pressures were measured by the same observer usingthe same Goldmann applanation tonometer.

3. Following recording of the baseline Diurnal Curve on timolol 0.5%bid, all of the patients were. instructed to add 1 drop of a solution toeach eye at 8:10 pm and 8:10 am, ten minutes after adding timolol, forseven days. The solution given to 16 of the patients contained 2%Compound I; the solution given to the other 15 patients was a placebosolution.

4. On Day 2, the IOP of each patient was measured at 8 am and 9 am, anda 12 hour diurnal curve was recorded on Day 8.

preliminary IOP data follow:

MEAN IOP PRESTUDY AND PERCENT CHANGE IN IOP ON DAY 8 FROM PRESTUDYCOMPOUND I PLUS TIMOLOL GROUP TIMOLOL TIMOLOL PLUS TIME BASELINECOMPOUND I 8am 27.4 −16.8% 9am 27.1 −21.0% 10am 25.4 −18.9% noon 25.6−17.3% 2pm 24.5 −18.6% 4pm 25.2 −17.0% 6pm 25.7 −18.2% 8pm 24.4 −13.2%PLACEBO PLUS TIMOLOL GROUP TIMOLOL TIMOLOL PLUS TIME BASELINE PLACEBO8am 26.9 −3.4% 9am 24.2 −4.5% 10am 23.3 −1.7% noon 23.2 +0.2% 2pm 21.6+0.1% 4pm 22.7 −0.1% 6pm 23.1 −3.7% 8pm 21.9 +6.6% These data arerepresented graphically in Figure 1.

Overall, Compound I given every 12 hours demonstrated a clinically andstatistically significant effect over the effect of timolol alone,ranging from 13%-21% based on worse eye analysis.

What is claimed is:
 1. A topical formulation for treatment of ocularhypertension or glaucoma comprising an opthalmologically acceptablecarrier, 0.05 to 5% of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide, the individual diastereomers, enantiomers or mixtures thereof,or an ophthalmologically acceptable salt thereof, and 0.01 to 1.0% of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanol,or an ophthalmologically acceptable salt thereof.
 2. A formulation ofclaim 1 wherein the salt of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis maleate.
 3. A formulation of claim 1 wherein the salt of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is the monohydrochloride salt.
 4. A formulation of claim 3wherein the concentration of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 0.5 to 3%.
 5. A formulation of claim 2 wherein theconcentration of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.1 to 0.5%.
 6. A formulation of claim 1 wherein the concentration of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 0.7 to 2.0% and the concentration of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.5%.
 7. A formulation of claim 6 which further contains a gum.
 8. Aformulation of claim 7 wherein the gum is gellan gum at a concentrationof 0.1% to 2%.
 9. A formulation of claim 1 which takes a form ofsolution, gel, ointment, suspension or solid insert.
 10. A formulationof claim 6 wherein the ratio of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide to(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis greater than one.
 11. A formulation of claim 10 wherein theconcentration of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 2% and(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.5%.
 12. A topical formulation for treatment of ocular hypertensionor glaucoma comprising an opthalmologically acceptable carrier, 2% of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide monohydrochloride, and 0.5% of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolmaleate, or an ophthalmologically acceptable salt thereof.
 13. Aformulation of claim 12 which further contains gellan gum at aconcentration of 0.1% to 2%.
 14. A method of treating ocularhypertension or glaucoma, which, comprises administration of aneffective amount of a topical ophthalmic formulation to a patient inneed thereof, comprising an ophthalmologically acceptable carrier, 0.05to 5% of(S,S)-(−)-5,6dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide, the individual diastereomers, enantiomers or mixtures thereof,or an ophthalmologically acceptable salt thereof, and 0.01 to 1.0% of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanol,or an ophthalmologically acceptable salt thereof.
 15. A method of claim14 wherein the salt of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis maleate.
 16. A method of claim 14 wherein the salt of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is the monohydrochloride salt.
 17. A method of claim 16 whereintie concentration of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 0.5 to 3%.
 18. A method of claim 15 wherein the concentrationof(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.1 to 0.5%.
 19. A method of claim 14 wherein the concentration of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 0.7 to 2.0% and the concentration of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.5%.
 20. A method of claim 14 wherein the formulation contains agum.
 21. A method of claim 20 wherein the gum is gellan gum at aconcentration of 0.1% to 2%.
 22. A method of claim 14 wherein theformulation takes a form of solution, gel, ointment, suspension or solidinsert.
 23. A method of claim 14 wherein the formulation takes the formof a solution adapted for topical administration.
 24. A method of claim20 wherein the ratio of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-2,3-b]thiopyran-2-sulfonamide-7,7dioxide to(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis greater than one.
 25. A method of claim 14 wherein the concentrationof(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide is 2% and(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolis 0.5%.
 26. A method of treating ocular hypertension or glaucoma, whichcomprises administration of an effective amount of a topical ophthalmicformulation to a patient in need thereof, comprising anophthalmologically acceptable carrier, 2% of(S,S)-(−)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b]thiopyran-2-sulfonamide-7,7dioxide monohydrochloride, 0.5% of(s)-(−)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-propanolmaleate.
 27. A method of claim 26 wherein the formulation containsgellan gum at a concentration of 0.1% to 2%.